Pharmaceutical compositions
Inventors
Brisander, Magnus • Demirbüker, Mustafa • Jesson, Gérald • Malmsten, Martin • Dérand, Helene
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12576071-B2
Publication Date
2026-03-17
Expiration Date
Abstract
The present invention relates to the field of methods for providing pharmaceutical compositions comprising poorly water-soluble drugs. In particular the present invention relates to compositions comprising stable, amorphous hybrid nanoparticles, comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component, useful in pharmaceutical compositions and in therapy.
Core Innovation
The invention relates to stable, essentially amorphous hybrid nanoparticles for poorly water-soluble protein kinase inhibitors. The hybrid nanoparticles include a PKI and a polymeric stabilizing and matrix-forming component, and optionally a solubilizer. The particles are very small and maintain an essentially amorphous character while providing stability over extended storage periods.
The invention relates to a tablet comprising particles that include amorphous nilotinib and a polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, methacrylic acid and methyl methacrylate copolymer, hydroxypropyl methylcellulose, or a combination thereof. The particles exclude a pharmaceutically acceptable solubilizer, and the amorphous nilotinib and the polymer are incorporated into the particles, together with one or more excipients.
The core concept is that forming stable amorphous hybrid nanoparticles with polymeric stabilizing or matrix-forming components improves dissolution and in vivo exposure without including a pharmaceutically acceptable solubilizer in the particles. The document reports enhanced solubilization and higher exposure, including performance in FaSSIF at pH about 6.5, while reducing dependency on stomach pH. Stability characterization is also described, including XRPD and dissolution/AUC retention after storage, together with glass transition behavior and hygroscopicity-related characterization.
Claims Coverage
The provided claim content centers on tablets whose particles incorporate amorphous nilotinib with a selected polymeric component while excluding a pharmaceutically acceptable solubilizer. The claim family further narrows the composition by permissible amorphous nilotinib forms, nilotinib weight percentages, polymer behavior, and therapeutic leukemia use. The provided independent claim content includes 2 inventive features.
Tablet particles with amorphous nilotinib and selected polymer
A tablet comprising particles including amorphous nilotinib and a polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, methacrylic acid and methyl methacrylate copolymer, hydroxypropyl methylcellulose, or a combination thereof.
Particles excluding a pharmaceutically acceptable solubilizer
The particles exclude a pharmaceutically acceptable solubilizer, and the amorphous nilotinib and the polymer are incorporated into the particles, with one or more excipients in the tablet.
Particles with amorphous nilotinib and specific permissible amorphous nilotinib forms
The amorphous nilotinib comprises nilotinib, a nilotinib salt, a nilotinib hydrate, a nilotinib solvate, or a combination thereof.
Particles containing amorphous nilotinib in a defined weight range
Nilotinib is present in an amount ranging from about 5% to about 70% by weight of the particles.
Polymer selection constrained to specified dissolution-rate behavior
The polymer does not delay the dissolution rate of the amorphous nilotinib in an aqueous medium.
Particles containing amorphous nilotinib in a narrower weight range
Nilotinib is present in the particles at about 10% to about 40% by weight.
Therapeutic leukemia use for tablets of the claimed composition
The leukemia is at least one selected from lymphocytic leukemia and myelogenous leukemia.
Overall, claim coverage centers on tablets whose particles incorporate amorphous nilotinib with one of a specified set of polymeric matrix or stabilizing components while excluding a pharmaceutically acceptable solubilizer, and further narrows the composition by permissible amorphous nilotinib forms, nilotinib weight percentages, dissolution-rate behavior, and leukemia subtype use.
Stated Advantages
Increased dissolution rate and/or solubility of the hybrid nanoparticles versus raw crystalline drug.
Maintained essentially amorphous state indicated by structural characterization such as XRPD after storage.
Improved apparent solubility and dissolution performance across intestinal, neutral pH, and gastric media.
In vivo plasma exposure is described for nilotinib-base hybrid nanoparticles after oral dosing compared with a marketed nilotinib HCl formulation.
Enhanced dissolution and increased solubilized drug (% solubilized) compared with non-formulated drug, as indicated by measured dissolution and related data in FaSSIF.
In vivo exposure improvements indicated by AUC increases relative to non-formulated drug and comparison to marketed nilotinib HCl formulations.
Reduced stomach pH dependency, as described for nilotinib base formulations in dog oral PK results.
Stability of the amorphous hybrid nanoparticles over storage, with dissolution/AUC profile retention after 11+ months.
Documented Applications
Pharmaceutical composition and therapeutic use in leukemia, including lymphocytic leukemia and myelogenous leukemia.
Apparent solubility and dissolution testing under intestinal and gastric conditions for poorly water-soluble protein kinase inhibitors.
Oral dosing in beagle dogs to evaluate plasma exposure for nilotinib-base hybrids versus a marketed nilotinib HCl formulation.
Formulation and performance characterization for kinase inhibitors including nilotinib base, crizotinib, axitinib, and vemurafenib, with dissolution assessment in FaSSIF at pH about 6.5.
In vivo oral pharmacokinetic performance in beagle dogs for nilotinib base formulations, with plasma exposure metrics including Cmax, Tmax, and AUC0-24h, compared with marketed nilotinib HCl.
Stability evaluation of amorphous hybrid nanoparticles, including XRPD, dissolution/AUC retention after storage, and related glass transition and hygroscopicity-related characterization.
Interested in licensing this patent?